Major depressive disorder (MDD) and type II diabetes (DM2), share numerous pathophysiological characteristics that reflect bidirectional links between the central nervous system (CNS) and endocrine homeostasis. Patients with DM2 have a high incidence of depression, and reciprocally, patients with depression are at increased risk of developing DM2. Insulin resistance (IR) or "pre-diabetes" is often accompanied by depressive symptomatology, and patients with depression have biomarkers suggestive of high IR. Greater understanding of these reciprocal links may lead to a dramatic shift in the way in which depression is conceptualized and treated, with a greater focus on proper metabolic function. The current application aims to investigate the effect of improved insulin resistance on mood upon treatment with a PPAR -agonist (pioglitazone) in a placebo-controlled design. Eighty patients with depression will be recruited in the study;half with insulin resistance and half without insulin resistance. Subjects will undergo clinical endocrinological evaluation (including oral glucose tolerance testing) and neuropsychological testing before and after 12 weeks of double-blind treatment. Patients'mood and metabolic function will be monitored throughout the study. We propose Identifying and treating insulin resistance in patients with depression may reduce the morbidity, mortality, and economic burden associated with depression. Further, the use of an insulin-sensitizing medication for the treatment of depression offers a remarkable shift in our view of how mood disorders can be treated. PUBLIC HEALTH RELEVANCE: The epidemic of obesity in the U.S. adds substantially to rise in overall morbidity and mortality. The National Cholesterol Education Program ATPIII (Adult Treatment Panel) Guidelines identify diabetes as a mortality risk equivalent to cardiovascular disease (CVD), in contrast to the previous conceptualization of diabetes as a risk factor for CVD. Patients with depression have significantly increased risk for CVD. The association exists for both men and women, spans various age groups, and occurs in a range of countries throughout the world. Patients with depression also have a significantly higher all-cause mortality rate. The results of this study may further establish the importance of identifying and treating insulin resistance in patients with depression to reduce the morbidity, mortality, and economic burden associated with depression. Further, the use of an insulin-sensitizing medication for the treatment of depression offers a remarkable shift in our view of how mood disorders can be treated. .